We are currently experiencing an epidemic of obesity and type 2 diabetes. Hypothalamic melanocortins integrate peripheral and central signals to maintain normal body weight, and are thought to be targets for treating obesity and insulin resistance. Two melanocortin receptors have been identified in the hypothalamus. Activation of melanocortin-4 receptors (MC4R) reduces appetite and stimulates energy expenditure. The MC3R is more abundant than the MC4R in the hypothalamus, however the function and potential use of this receptor for treating insulin resistance is not clear. We originally reported that MC3RKO mice are mildly obese, and have since tested the hypothesis that MC3R expressed in the hypothalamus regulate insulin sensitivity. For this purpose, we backcrossed MC3R knockout (KO) 10 generations onto the C57BL/6J background. C57BL/6J mice rapidly develop insulin resistance and, with long term exposure (6 months) to a high fat diet, develop DM2. This strain is commonly used as genetic model of diet-induced obesity and insulin resistance. Our preliminary data are interesting in that they suggest that MC3R activity might be a significant factor in the development of insulin resistance in diet-induced obese insulin resistant C57BL/6J mice. Obese MC3RKO have increased insulin sensitivity compared to leaner wild type littermates after being fed a high fat diet for 2 months. Moreover, obese MC3RKO do not develop some of the pathologies normally associated with obesity: hepatomegaly, elevated free fatty acids, increased liver fatty acid synthase mRNA expression, and reduced liver IRS2 protein. Our preliminary studies only examined the short term effects of high fat diets. We are now proposing experiments to determine whether inactivation of the MC3R gene in C57BL/6J mice will prevent or delay the development of insulin resistance and DM2 induced by 6 months on a high fat diet. We will use hyperinsulinemic-euglycemic clamps to demonstrate that insulin sensitivity and glucose disposal are not inhibited by a high fat diet, as observed in wild type C57BL/6J mice. Finally, we will determine whether chronic treatment of obese mice with recently developed MC3R agonists and antagonists will promote or improve insulin sensitivity. The results of these experiments will provide the first definitive evidence that manipulation of the MC3R might be a viable approach for treating insulin resistance.